Structural organization of the mouse and human GALR1 galanin receptor genes (Galnr and GALNR) and chromosomal localization of the mouse gene

The neuropeptide galanin elicits a range of biological effects by interaction with specific G-protein-coupled receptors. Human and rat GALR1 galanin receptor cDNA clones have previously been isolated using expression cloning. We have used the human GALR1 cDNA in hybridization screening to isolate the gene encoding GALR1 in both human (GALNR) and mouse (Galnr). The gene spans approximately 15-20 kb in both species; its structural organization is conserved and is unique among G-protein-coupled receptors. The coding sequence is contained on three exons, with exon 1 encoding the N-terminal end of the receptor and the first five transmembrane domains. Exon 2 encodes the third intracellular loop, while exon 3 encodes the remainder of the receptor, from transmembrane domain 6 to the C-terminus of the receptor protein. The mouse and human GALR1 receptor proteins are 348 and 349 amino acids long, respectively, and display 93% identity at the amino acid level. The mouse Galnr gene has been localized to Chromosome 18E4, homoeologous with the previously reported localization of the human GALNR gene to 18q23 in the same syntenic group as the genes encoding nuclear factor of activated T-cells, cytoplasmic 1, and myelin basic protein.     

Spreading depression determines acute cellular damage in the hippocampal slice during oxygen/glucose deprivation

During ischaemia neurons depolarize and release the neurotransmitter L-glutamate, which accumulates extracellularly and binds to postsynaptic receptors. This initiates a sequence of events thought to culminate in immediate and delayed neuronal death. However, there is growing evidence that during ischaemia the development of spreading depression (SD) can be an important determinant of the degree and extent of ischaemic damage. In contrast, SD without metabolic compromise (as occurs in migraine aura) causes no discernible damage to brain tissue. SD is a profound depolarization of neurons and glia that propagates like a wave across brain tissue. Brain cell swelling, an early event of both the excitotoxic process and of SD, can be assessed by imaging associated intrinsic optical signals (IOSs). We demonstrate here that IOS imaging clearly demarcates the ignition site and migration of SD across the submerged hippocampal slice of the rat. If SD is induced by elevating [K+]O, the tissue fully recovers, but in slices that are metabolically compromised at 37.5 degrees C by oxygen/glucose deprivation (OGD) or by ouabain exposure, cellular damage develops only where SD has propagated. Specifically, the evoked CA1 field potential is permanently lost, the cell bodies of involved neurons swell and their dendritic regions increase in opacity. In contrast to OGD, bath application of L-glutamate (6-10 mM) at 37.5 degrees C evokes a non-propagating LT increase in CA1 that reverses without obvious cellular damage. Moreover, application of 2-20 mM glutamate or various glutamate agonists fail to evoke SD in the submerged hippocampal slice. We propose that SD and OGD together (but not alone) constitute a 'one-two punch', causing acute neuronal death in the slice that is not replicated by elevated glutamate. These findings support the proposal that SD generation during stroke promotes and extends acute ischaemic damage.     

Tumor efficacy and bone marrow-sparing properties of TER286, a cytotoxin activated by glutathione S-transferase

TER286 is a latent drug activated by human glutathione S-transferase (GST) isoforms P1-1 and A1-1 to produce a nitrogen mustard alkylating agent. M7609 human colon carcinoma, selected for resistance to doxorubicin, and MCF-7 human breast carcinoma, selected for resistance to cyclophosphamide, both showed increased sensitivity to TER286 over their parental lines in parallel with increased expression of GST P1-1. In primary human tumor clonogenic assays, the spectrum of cytotoxic activity observed for TER286 was both broad and unusual when compared to a variety of current drugs. In murine xenografts of M7609 engineered to have high, medium, or low GST P1-1, responses to TER286 were positively correlated with the level of P1-1. Cytotoxicity was also observed in several other cell culture and xenograft models. In xenografts of the MX-1 human breast carcinoma, tumor growth inhibition or regression was observed in nearly all of the animals treated with an aggressive regimen of five daily doses. This schedule resulted in a 24-h posttreatment decline in bone marrow progenitors to 60% of control and was no worse than for a single dose of TER286. These studies have motivated election of TER286 as a clinical candidate.     

Immunoproliferative small intestinal disease: a frequently missed diagnosis

Immunoproliferative small intestinal disease (IPSID) is a poorly recognized cause of malabsorption syndrome in India. Clinicopathological features of five patients with IPSID seen over a two-year period are described. Our data suggest that IPSID is commonly misdiagnosed as intestinal tuberculosis due to lack of awareness and reluctance to obtain small bowel biopsies. Empirical institution of anti-tubercular chemotherapy not only leads to delayed diagnosis but also possibly alters the natural history of the disease, resulting in an intermediate phase of amelioration followed by a terminal phase of lymphomatous transformation. The disease is therefore usually diagnosed at an advanced stage and hence is associated with a relatively poor outcome.     

Focal occlusive disease of the common femoral artery: a report of 20 cases

Occlusive disease localized to the common femoral artery without contiguous involvement of the external iliac and superficial femoral arteries is distinctly uncommon in vascular surgical practice. Twenty patients with focal occlusive disease in 21 common femoral arteries are featured in this report. All except one had severe disabling symptoms: Fontaine classification was stage I in one patient, stage IIb in 13, and stage III in six patients. The probable aetiology, based on clinical features and angiographic observations, was identified as atherosclerosis (nine cases), thromboangiitis obliterans (three) and Takayasu's arteritis (two). Histological features of mucoid vasculopathy, a novel disorder, was seen in one patient while no specific aetiology was evident in five patients. Associated lesions were seen in fourteen patients: aortoiliac in one, femoropopliteal in seven (without any continuity to the common femoral lesion), internal iliac in three and tibial in three. Balloon angioplasty of the common femoral artery lesions was attempted in 14 patients with successful outcome in nine. Three patients (including two with failed balloon angioplasty), underwent thromboendarterectomy and two bypass procedures (iliofemoral, one; femoropopliteal, one). Late reocclusion occurred in one patient each in the angioplasty and surgical groups. There were no procedure-related complications in either group.     

Conservation of the 168 divIB gene in Bacillus subtilis W23 and B. licheniformis, and evidence for homology to ftsQ of Escherichia coli

Recent reports indicate that combined anterior cruciate ligament/medial collateral ligament (ACL/MCL) knee injuries are usually associated with a lateral meniscus tear. In our center, snow skiing is the athletic activity most frequently associated with this double-ligament injury complex. A sports-specific analysis was undertaken to evaluate the hypothesis that the snow skiing ligament injury is different from similar injuries caused by other athletic activities. Of a total of 64 acute arthroscopically confirmed tears of both the MCL and ACL, 23 were caused by snow skiing and 41 by nonskiing activities. There were fewer lateral meniscus tears in skiers (43%) when compared with the nonskiers (88%). Skiers also had fewer medial meniscus tears (13%) than did nonskiers (37%). No medial meniscus tears occurred in the absence of a lateral meniscus tear. Although 78% of the skiers were women, only 12% of the nonskiers were women. Skiers were older (average age 35 years) than the nonskiers (average age 28 years). The right knee was injured almost twice as frequently as the left. These data suggest that the double (ACL/MCL) ligament injury in skiers might be distinctly different from that in nonskiers.     

Immunologic protection of the premature newborn by human milk

During the past decade, considerable evidence has accrued regarding the immunologic uniqueness of human milk and of the important role that the immune system in human milk plays in protecting not only the mature, healthy newborn, but also the premature infant who is more prone to infections and the damage caused by inflammatory processes. However, there is a great deal more to learn about the prophylactic and therapeutic uses of human milk in low birth weight infants, including (1) the status of many of the host defense factors in preterm milk, (2) how to preserve the protective agents in human milk during processing and storage, (3) the dose and duration of treatment with human preterm or mature milk that will be needed to protect against a particular disorder, (4) whether non-maternal milk is as efficacious as maternal milk for these infants, and (5) in view of the concern of potential graft versus host reactions, whether it is desirable or contraindicated to maintain the leukocytes in human milk used to feed premature infants. These questions are not easily answered, but will be worthy considerations by neonatologists, clinical immunologists, epidemiologists, and others who are concerned with providing optimal nutritional/immunologic support for the premature infant.